Alzheimer's disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of AD include deposition of amyloid b-peptide (Ab) in neuritic plaques and cerebral blood vessels, neurofibrillary tangles and loss of neurons. Increasing evidence supports the notion that Ab and its precursor play important roles in the pathogenesis of AD. Immunization of AD mouse models with synthetic Ab prevented or reduced Ab deposits and improved their memory and learning deficits. Human clinical trials of Ab immunization (AN1792) were halted due to brain inflammation. In addition, the clinical trials and passive immunization induced cerebral hemorrhages in one AD patient and some AD mouse models, respectively. Recent reports of the clinical trials indicate that Ab immunization is effective in clearing Ab deposits and improving cognitive deficits in AD patients Thus, it is crucial to find a safe and effective immune therapy. Because peripheral administration of antibodies against Ab also induced clearance of preexisting amyloid plaques in AD mouse models and because meningoencephalitis associated with the AN1792 trial is thought to be T-cell-mediated auto-immune responses, immunization modalities that elicit predominantly T helper (Th) type 2 immune responses are considered to be safer for AD prevention and treatment. Another obstacle for AD immunotherapy is the difficulty to induce an appropriate anti-Ab titer in AD patients. In the phase II clinical trial, 19.7% of AD patients developed a positive Ab titer. In attempting to develop such safe, effective vaccines, we demonstrated that adenovirus-vectored vaccines encoding Ab can induce Th2-polarized anti-inflammatory immune responses in several strains of mice. We found that a DNA prime-adenovirus boost regimen increased the number of mice positive for anti-Ab antibody, the value of the antibody titer and the affinity of the antibody to amyloid plaques compared with only adenovirus immunization. Thus, the heterologous DNA prime-adenovirus boost regimen is superior to its homologous counterpart. We hypothesize that a heterologous DNA prime-adenovirus boost regimen is effective in reducing Ab deposits and in improving behavioral deficits in AD mouse models and that statins enhance Th2-type responses induced by a DNA prime-adenovirus boost regimen and protect animals against brain inflammation and hemorrhages. In Aim 1, we will evaluate the efficacy and safety of DNA prime-adenovirus boost immunization in AD model mice. In Aim2, We will evaluate the efficacy and safety of combined treatment of DNA prime-adenovirus boost immunization with simvastatin in AD model mice. We will perform immunological, histopathological, immunohistochemical, biochemical and behavioral analyses on the animals to determine the efficacy and safety of the modalities. The efficacy and safety of the immunization with simvastatin will be compared with those without statins The goal of this project is to establish the logical basis for developing safe, effective modalities for AD by testing combination therapy of DNA prime-adenovirus boost regimens with statins. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. This study will serve as a proof of principle to demonstrate if DNA prime-virus boost immunization with statins can induce potentially safer and more efficacious immune responses to treat AD than that without statins.